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Effect of Microgravity on Drug Responses Using Engineered Heart Tissues

微重力对工程心脏组织药物反应的影响

基本信息

批准号：
10173394
负责人：
Beth L Pruitt
金额：
$ 72.06万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-18 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10173394
关键词：
3-Dimensional Adrenergic beta-Antagonists Affect African American Age-Years Angiotensin-Converting Enzyme Inhibitors Animal Model Animals Architecture Astronauts Atrophic Back Biological Biological Assay Biology Cachexia Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular Diseases Cardiovascular system Carotid Arteries Caucasians Cell Adhesion Cell Communication Cell Culture Techniques Cell physiology Cells Classification Clinical Complex Disease Doctor of Philosophy Drug Combinations Drug Interactions Drug Screening Electrophysiology (science)Endothelial Cells Engineering Environment Exposure to Extracellular Matrix Female Fibroblasts Force of Gravity Gene Expression Heart Heart failure Hispanic Americans Hispanics Human In Vitro Individual Institutes International Laboratories Mammalian Cell Measures Mechanics Metabolic Microgravity Microscopic Mission Mitochondria Modeling Molecular Morphology Muscular Atrophy Myocardium Normal Cell Organ Organoids Patients Pattern Pharmaceutical Preparations Pharmacogenomics Phase Phenotype Physiological Physiological Adaptation Physiology Planet Earth Plasmids Prevention Proteins Proteomics Protocols documentation Race Reporting Research Risk Sampling Signal Pathway Somatic Cell Space Flight Structure Technology Testing Therapeutic Time Tissue Engineering Tissue Microarray Tissue Model Tissues Translating Tungsten Universities Weight base blastomere structure blood pressure reduction cardiac tissue engineering cardiogenesis cardiovascular health caucasian American cell type cohort disease phenotype drug candidate drug discovery drug testing drug use screening endothelial stem cell ethnic diversity extracellular healthy volunteer heart function human disease in vitro Model induced pluripotent stem cell insight interest ischemic cardiomyopathy male member miniaturize patient response preservation prevent professor racial diversity recruit response scaffold secretory protein self assembly sex space station space travel spatiotemporal three dimensional structure three-dimensional modeling tool transcriptome sequencing transcriptomics two-dimensional

项目摘要

PROJECT SUMMARY Tissue engineered organs or functional tissue-like ensembles contribute significantly to our understanding of cellular niches that allow cells to migrate, develop and mature in three dimensions (3-D). Conventional two- dimensional (2-D) mammalian cell culture does not represent the physiological environments that form the basis for normal cell function. A 3-D environment promotes isotropic cell-cell communications, provides extracellular guidance from structural matrix scaffolding, and allows spatiotemporal remodelling. Our specific interest is in investigating the effects of microgravity on heart function with the use of Engineered Heart Tissues (EHTs). Since these tissue engineering platforms support multicellular architecture from a ‘bottom-up’ approach, it is critical to understand the mechanisms of heart development from a primordial state. Although animal models are used widely to investigate biological responses to therapeutics, inherent differences between human and animal biology combined with the unlikelihood of animals developing a human disease limit the ability to validate research findings. Human induced pluripotent stem cells (hiPSCs) have emerged as an indispensable tool to drive cells from an embryonic state to any somatic cell type. Our laboratory’s focus and expertise in generating hiPSC-derived cardiomyocytes (hiPSC-CMs) and modelling of cardiomyopathies has yielded deeper insight into several rare and common causes of heart failure. To maintain a tissue-specific microenvironment, dissociated cells must be cultured in a physiologically relevant 3-D extracellular matrix (ECM). In the first phase (UG3), we will generate hiPSC-CMs from healthy patients belonging to diverse racial groups (Caucasians, Hispanics, and African Americans). The hiPSC-CMs will be used to fabricate our well-characterized EHT platforms, to understand cellular mechanisms that affect cardiac function both under microgravity and earth’s gravity. Alterations in cardiac function due to weakened heart muscles in the samples exposed to microgravity will be matched with molecular and electrophysiological disease patterns observed in ischemic cardiomyopathy. In the second phase (UH3), the well-characterized microgravity-induced disease phenotype will be translated on Heart Tissue Arrays (HTA) to screen for potential drug candidates in a high-throughput manner. The proposed study will for the first time reveal key functional and molecular differences that drive phenotypic changes in heart tissues on EHT assemblies under influence of microgravity.

项目概要组织工程器官或功能性类组织整体有助于我们理解允许细胞在三维 (3-D) 上迁移、发育和成熟的细胞生态位。常规二- 三维（2-D）哺乳动物细胞培养并不代表构成基础的生理环境为了正常的细胞功能。 3D 环境促进各向同性细胞间通讯，提供细胞外来自结构矩阵脚手架的指导，并允许时空重塑。我们的具体兴趣在于使用工程心脏组织 (EHT) 研究微重力对心脏功能的影响。自从这些组织工程平台以“自下而上”的方式支持多细胞结构，这一点至关重要从原始状态了解心脏发育的机制。虽然使用动物模型广泛研究对治疗的生物反应以及人类和动物之间的固有差异生物学加上动物不太可能患上人类疾病，限制了验证的能力研究结果。人类诱导多能干细胞（hiPSC）已成为不可或缺的工具驱动细胞从胚胎状态转变为任何体细胞类型。我们实验室在生成方面的重点和专业知识 hiPSC 衍生的心肌细胞 (hiPSC-CM) 和心肌病模型使人们对以下问题有了更深入的了解心力衰竭的几种罕见和常见原因。为了维持组织特异性的微环境，解离细胞必须在生理相关的 3-D 细胞外基质 (ECM) 中培养。在第一阶段（UG3），我们将从属于不同种族群体（白人、西班牙裔和白人）的健康患者中产生 hiPSC-CM 非裔美国人）。 hiPSC-CM 将用于制造我们特性良好的 EHT 平台，以了解在微重力和地球重力下影响心脏功能的细胞机制。由于暴露于微重力的样品中心肌减弱而导致心脏功能的改变与缺血性心肌病中观察到的分子和电生理疾病模式相匹配。在第二阶段（UH3），充分表征的微重力诱发的疾病表型将在心脏上转化组织阵列 (HTA) 以高通量方式筛选潜在的候选药物。拟议的研究将首次揭示驱动心脏组织表型变化的关键功能和分子差异微重力影响下的 EHT 组件。